rs121434313
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152594.3(SPRED1):c.70C>T(p.Arg24Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000186 in 1,613,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SPRED1
NM_152594.3 stop_gained
NM_152594.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.92
Genes affected
SPRED1 (HGNC:20249): (sprouty related EVH1 domain containing 1) The protein encoded by this gene is a member of the Sprouty family of proteins and is phosphorylated by tyrosine kinase in response to several growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade. Defects in this gene are a cause of neurofibromatosis type 1-like syndrome (NFLS). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 98 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-38299410-C-T is Pathogenic according to our data. Variant chr15-38299410-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38299410-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPRED1 | NM_152594.3 | c.70C>T | p.Arg24Ter | stop_gained | 2/7 | ENST00000299084.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPRED1 | ENST00000299084.9 | c.70C>T | p.Arg24Ter | stop_gained | 2/7 | 1 | NM_152594.3 | P1 | |
SPRED1 | ENST00000561317.1 | c.7C>T | p.Arg3Ter | stop_gained | 3/6 | 4 | |||
SPRED1 | ENST00000561205.1 | n.408C>T | non_coding_transcript_exon_variant | 2/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152000Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461694Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727136
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152000Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74246
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Legius syndrome Pathogenic:5
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2023 | Variant summary: SPRED1 c.70C>T (p.Arg24X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251158 control chromosomes (gnomAD). c.70C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) and has been found to segregate with the disease phenotype in at least one family (e.g. Brems_2007). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 17704776). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Legius syndrome (MIM#611431). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other 5' NMD-escape variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in several individuals with a neurofibromatosis-like phenotype, cafe-au-lait or Legius syndrome (ClinVar, PMID: 28378438, PMID: 17704776, PMID: 31370276). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000001810 / PMID: 17704776). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1810). This premature translational stop signal has been observed in individuals with Legius syndrome (PMID: 17704776, 19920235, 21089071). This variant is present in population databases (rs121434313, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg24*) in the SPRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPRED1 are known to be pathogenic (PMID: 17704776). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | SPRED1: PVS1, PP1:Strong, PM2 - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at